INHIBITORS OF PROTEIN-KINASE-C .2. SUBSTITUTED BISINDOLYMALEIMIDES WITH IMPROVED POTENCY AND SELECTIVITY
INHIBITORS OF PROTEIN-KINASE-C .2. SUBSTITUTED BISINDOLYMALEIMIDES WITH IMPROVED POTENCY AND SELECTIVITY
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DOI：
10.1021/jm00084a004
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发表时间：
1992-03-20
影响因子：
7.3
通讯作者：
WILKINSON, SE
中科院分区：
文献类型：
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作者：
DAVIS, PD;ELLIOTT, LH;WILKINSON, SE
天然产物staurosporine抑制蛋白激酶C （PKC）的假设模式已被用作设计具有比母体化合物更高效力的取代双吲哚基马来酰亚胺的基础。结构-活性关系与抑制剂中的阳离子基团与酶中的羧酸基团相互作用一致，最有效的化合物的K(i)为3 nM。尽管PKA和PKC的ATP结合区具有广泛的序列同源性，但这些抑制剂与ATP竞争，但只有在更高浓度时才能抑制camp依赖性蛋白激酶（PKA）。我们进一步评估了三种化合物，发现它们可以抑制人类同种异体混合淋巴细胞反应，这表明PKC抑制剂在免疫抑制治疗中的潜在效用。其中一种化合物在大鼠中口服吸收，代表了PKC抑制剂作为药物发展的一个有吸引力的先导。
A hypothetical mode of inhibition of protein kinase C (PKC) by the natural product staurosporine has been used as a basis for the design of substituted bisindolylmaleimides with improved potency over the parent compound. Structure-activity relationships were consistent with the interaction of a cationic group in the inhibitor with a carboxylate group in the enzyme, and the most potent compound had a K(i) of 3 nM. The inhibitors were competitive with ATP but inhibited cAMP-dependent protein kinase (PKA) only at much higher concentrations despite the extensive sequence homology between the ATP-binding regions of PKA and PKC. Three compounds were evaluated further and found to inhibit a human allogeneic mixed lymphocyte reaction pointing to the potential utility of PKC inhibitors in immunosuppressive therapy. One of these compounds was orally absorbed in the rat and represents an attractive lead in the development of PKC inhibitors as drugs.